Signaling in rat brainstem via Gpr160 is required for the anorexigenic and antidipsogenic actions of cocaine- and amphetamine-regulated transcript peptide

Abstract

Recent work identified Gpr160 as a candidate receptor for cocaine- and amphetamine-regulated transcript peptide (CARTp) and described its role in pain modulation. The aims of the present study were to determine if Gpr160 is required for the CARTp's ability to reduce food and water intake and to initially identify the distribution of Gpr160-like immunoreactivity (Gpr160ir) in the rat brain. A passive immunoneutralization approach targeting Gpr160 was used to block the behavioral effects of a pharmacologic dose of CARTp in the fourth cerebroventricle (4V) of rats and to determine the importance of endogenously produced CARTp in the control of ingestive behaviors. Passive immunoneutralization of Gpr160 in the 4V blocked the actions of CARTp to inhibit food and water intakes. Blockade of Gpr160 in the 4V, independent of pharmacologic CART treatment, caused an increase in both overnight food and water intakes. The decrease in food, but not water intake, caused by central injection of CARTp was demonstrated to be interrupted by prior administration of a GLP-1 receptor antagonist. Gpr160ir was observed in several, distinct sites throughout the rat brain, where CARTp staining has been described. Importantly, Gpr160ir was observed to be present in both neuronal and non-neuronal cell types. These data support the hypothesis that Gpr160 is required for the anorexigenic actions of central CARTp injection, and extend these findings to water drinking. Gpr160ir was observed in both neuronal and non-neuronal cell types in regions known to be important in the multiple pharmacologic effects of CARTp, identifying those areas as targets for future compromise of function studies.

Behavioral characterization of G-protein-coupled receptor 160 knockout mice

“…Although CARTp is a widely known anorectic peptide, only recently was GPR160 shown to be involved in feeding and required for CARTp's anorexigenic behavior. 33,59,61 Compared with age-matched controls, the Gpr160 KO mice did not differ in body weight in either sex up to 5 months after birth when fed a chow diet. Different strains of Cartp KO mice also showed no body weight changes at a young age compared with controls when fed a chow diet.…”

“…Cocaine-and amphetamine-regulated transcript peptide and GPR160 are found in areas important in memory recognition. 6,33 Several studies have shown that exogenous CARTp promotes memory formation and has a neuroprotective effect. 6,39 In this study, neither sex of the global Gpr160 KO mice showed differences in learning and memory.…”

“Peptidergic modulation of motor neuron output via CART signaling at C bouton synapses”

“…Regarding CART receptors, recent studies have pinpointed the G-Protein-Coupled-Receptor (GPCR) Gpr160 as a putative receptor for the CART peptide, proposing that CARTp/Gpr160 signaling in the dorsal horn of the spinal cord mediates neuropathic pain through a c-fos and ERK/CREB pathway 64 . Furthermore, CARTp/Gpr160 coupling in the rat brainstem has been proven necessary for the anorexigenic and antidipsogenic effects of exogenous CART administration 65 . The identification of the CART peptide receptor in the ventral horn and in particular in the motor neuron membrane remains to be determined; however, its discovery will have the potential to reveal the intracellular signaling mechanisms initiated by CART-motor neuron communication.…”

Identification of Key Genes and Underlying Mechanisms in Cystic Fibrosis and its Associated Complications Based on Bioinformatics Analysis of Next Generation Sequencing Data Analysis

“…MMP9 [262], IGF2 [273], SOCS3 [274], MMP8 [265], OSM (oncostatin M) [266], PLAU (plasminogen activator, urokinase) [275], ADAMDEC1 [269], IL1RN [270], TLR4 [271], CD80 [276] and TXNIP (thioredoxin interacting protein) [272] make great contributions to the progression of nasal polyps. MMP9 [277], S100A12 [278], IGF2 [279], GPR84 [280], SOCS3 [281], ANXA3 [282], IGFBP2 [283], NOS1AP [284], G0S2 [285], HP (haptoglobin) [286], MMP8 [287], SLC6A19 [288], OSM (oncostatin M) [289], S100A8 [290], FFAR3 [291], ARG1 [292], ADM (adrenomedullin) [293], S100A9 [294], NRG1 [295], IL1R1 [296], IL4R [297], TSPO (translocator protein) [298], TXN (thioredoxin) [299], PLAU (plasminogen activator, urokinase) [300], SLC11A1 [301], TRPM2 [302], RETN (resistin) [303], NLRC4 [304], CD55 [305], ALOX5AP [306], GPR160 [307], TRPM6 [308], ALOX5 [309], IL1RN [310], ADM2 [311], DGAT2 [312], TLR4 [313], ENTPD1 [314], GRB10 [315], IL17RA [316], IRS2 [317], MGAM (maltase-glucoamylase) [318], FADS2 [319], SLC22A4 [320], KCNJ15 [321], PPP1R3B [322], CTSD (cathepsin D) [323], SERPINB11 [324], COL4A3 [325], ADAM12 [326], SOX5 [327], CD80 [328], ERBB2 [329], POU2AF1 [330], FASLG (Fas ligand) [331], SOX13 [332], BANK1 [333], IL2RA [334], AQP3 [335], CCR4 [336], CD74 [337], FCRL3 [338], ITGB7 [339],...…”